(BQ) Part 2 book Cardiovascular diseases - From molecular pharmacology to evidence-Based therapeutics presents the following contents: Ischemic Heart Disease - Stable ischemic heart disease, ischemic heart disease - acute coronary syndromes, heart failure, cardiac arrhythmias, ischemic stroke.
UNIT IV ISCHEMIC HEART DISEASE: STABLE ISCHEMIC HEART DISEASE 13 Overview of Ischemic Heart Disease, Stable Angina, and Drug Therapy 13.1â•… Introduction Ischemic heart disease (IHD) is the single most common cause of death in developed nations as well as in many devel oping countries [1, 2] IHD is an umbrella term that encom passes a spectrum of cardiac disorders caused by myocardial ischemia The notable examples of IHD include stable IHD (SIHD) (with stable angina as its prototypical manifestation) and acute coronary syndromes (ACS), among many others This chapter provides an overview of IHD and discusses the pathophysiology of SIHD and the mechanistically based drug targeting of stable angina Chapter 14 reviews antiangi nal drugs that have already been discussed in previous chap ters and also considers some newly approved antianginal drugs that are not covered in previous chapters The principles and guidelines regarding the management of SIHD/stable angina in clinical practice are given in Chapter 15 13.2â•… Classification, Epidemiology, and Pathophysiology 13.2.1â•… Classification 13.2.1.1â•… Definition of IHD and the International Statistical Classification of Diseases and Related Health Problems–10th Revision Classificationâ•… As noted earlier, the term IHD refers to a spectrum of diseases of the heart caused by decreased oxygen supply to the myocardium The International Statistical Classification of Diseases and Related Health Problems–10th Revision (ICD‐10) classifies IHD into the following six categories, and each category consists of multiple disease entities (also in Table 13.1): 1.╇ Angina pectoris 2.╇ Acute myocardial infarction 3.╇ Certain current complications following acute myocar dial infarction 4.╇ Subsequent myocardial infarction 5.╇ Other acute IHD 6.╇ Chronic IHD including coronary artery disease (CAD), among others 13.2.1.2â•… Conventional Classification of IHDâ•…ICD‐10 classification of IHD is comprehensive and authorita tive; however, it is complicated and often times causes confusion Hence, a simplified classification scheme is frequently used to divide IHD into two general categories (Fig 13.1): (1) SIHD with stable angina as the prototypical manifestation and (2) ACS that include unstable angina, non‐ST‐elevation myocardial infarction, and ST‐elevation myocardial infarction (see Unit V) SIHD is also frequently known as stable coronary artery disease (SCAD) Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD Indeed, the main symp tomatic clinical presentations of SIHD include (i) classical chronic stable angina caused by epicardial stenosis; (ii) angina caused by microvascular dysfunction (also known as microvascular angina), (iii) angina caused by vasospasm (vasospastic angina), and (iv) symptomatic ischemic cardiomyopathy [3] Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics, First Edition Y Robert Li © 2015 John Wiley & Sons, Inc Published 2015 by John Wiley & Sons, Inc 245 246 Overview of Ischemic Heart Disease, Stable Angina, and Drug Therapy Table 13.1â•… ICD‐10 classification of ischemic heart diseases (I20–I25)a ICD‐10 code ICD‐10 subcode and disease description I20: Angina pectoris I20.0 Unstable angina Angina: • Crescendo • De novo effort • Worsening effort Intermediate coronary syndrome Preinfarction syndrome I20.1 Angina pectoris with documented spasm Angina: • Angiospastic • Prinzmetal • Spasm induced • Variant 120.8 Other forms of angina pectoris Angina of effort Stenocardia 120.9 Angina pectoris, unspecified Angina: • NOS • Cardiac Anginal syndrome Ischemic chest pain I21: Acute myocardial infarction I21.0 Acute transmural myocardial infarction of anterior wall Transmural infarction (acute) (of): • Anterior (wall) NOS • Anteroapical • Anterolateral • Anteroseptal I21.1 Acute transmural myocardial infarction of inferior wall Transmural infarction (acute) (of): • Diaphragmatic wall • Inferior (wall) NOS • Inferolateral • Inferoposterior I21.2 Acute transmural myocardial infarction of other sites Transmural infarction (acute) (of): • Apical–lateral • Basal–lateral • High lateral • Lateral (wall) NOS • Posterior (true) • Posterobasal • Posterolateral • Posteroseptal • Septal NOS I21.3 Acute transmural myocardial infarction of unspecified site Transmural myocardial infarction NOS I21.4 Acute subendocardial myocardial infarction Nontransmural myocardial infarction NOS I21.9 Acute myocardial infarction, unspecified Myocardial infarction (acute) NOS I22: Subsequent myocardial infarction I22.0 Subsequent myocardial infarction of anterior wall Subsequent infarction (acute) (of): • Anterior (wall) NOS • Anteroapical • Anterolateral • Anteroseptal Classification, Epidemiology, and Pathophysiology 247 Table 13.1â•… (Continued) ICD‐10 code ICD‐10 subcode and disease description I22.1 Subsequent myocardial infarction of inferior wall Subsequent infarction (acute) (of): • Diaphragmatic wall • Inferior (wall) NOS • Inferolateral • Inferoposterior I22.8 Subsequent myocardial infarction of other sites Subsequent myocardial infarction (acute) (of): • Apical–lateral • Basal–lateral • High lateral • Lateral (wall) NOS • Posterior (true) • Posterobasal • Posterolateral • Posteroseptal • Septal NOS I22.9 Subsequent myocardial infarction of unspecified site I23: Certain current complications following acute myocardial infarction I23.0 Hemopericardium as current complication following acute myocardial infarction Excl.: the listed conditions, when: I23.1 Atrial septal defect as current complication following acute myocardial • Concurrent with acute myocardial infarction (I21‐I22) infarction • Not specified as current complications following acute I23.2 Ventricular septal defect as current complication following acute myocardial infarction myocardial infarction (I31.‐, I51.‐)b, c I23.3 Rupture of cardiac wall without hemopericardium as current complication following acute myocardial infarction Excl.: with hemopericardium (I23.0) I23.4 Rupture of chordae tendineae as current complication following acute myocardial infarction I23.5 Rupture of papillary muscle as current complication following acute myocardial infarction I23.6 Thrombosis of the atrium, auricular appendage, and ventricle as current complications following acute myocardial infarction I23.8 Other current complications following acute myocardial infarction I24: Other acute ischemic heart diseases Excl.: angina pectoris (I20.‐), transient myocardial ischemia of newborn (P29.4)d I24.0 Coronary thrombosis not resulting in myocardial infarction Coronary (artery)(vein): • Embolism • Occlusion • Thromboembolism Excl.: specified as chronic or with a stated duration of >4 weeks (>28 days) from onset (I25.8) I24.1 Dressler syndrome Postmyocardial infarction syndrome I24.8 Other forms of acute ischemic heart disease Coronary: • Failure • Insufficiency I24.9 Acute ischemic heart disease, unspecified Excl.: ischemic heart disease (chronic) NOS (I25.9) I25: Chronic ischemic heart disease Excl.: cardiovascular disease NOS (I51.6)e I25.0 Atherosclerotic cardiovascular disease, so described I25.1 Atherosclerotic heart disease Coronary (artery): • Atheroma • Atherosclerosis • Disease • Sclerosis (Continued) 248 Overview of Ischemic Heart Disease, Stable Angina, and Drug Therapy Table 13.1â•… (Continued) ICD‐10 code ICD‐10 subcode and disease description I25.2 Old myocardial infarction Healed myocardial infarction Past myocardial infarction diagnosed by ECG or other special investigation, but currently presenting no symptoms I25.3 Aneurysm of the heart Aneurysm: • Mural • Ventricular I25.4 Coronary artery aneurysm Coronary arteriovenous fistula, acquired Excl.: congenital coronary (artery) aneurysm (Q24.5)f I25.5 Ischemic cardiomyopathy I25.6 Silent myocardial ischemia I25.8 Other forms of chronic ischemic heart disease Any condition in I21‐I22 and I24.‐ specified as chronic or with a stated duration of >4 weeks (>28 days) from onset I25.9 Chronic ischemic heart disease, unspecified Ischemic heart disease (chronic) NOS Excl., excluding; NOS, not otherwise specified a Adapted from http://apps.who.int/classifications/icd10/browse/2010/en b I31.‐: Other diseases of pericardium under Other forms of heart disease (I30–I52) of Chapter IX: Diseases of the circulatory system (I00–I99) c I51.‐: Complications and ill‐defined descriptions of heart disease under Other forms of heart disease (I30‐I52) of Chapter IX: Diseases of the circulatory system (I00–I99) d P29.4: Transient myocardial ischemia of newborn under Respiratory and cardiovascular disorders specific to the perinatal period (P20–P29) of Chapter XVI: Certain conditions originating in the perinatal period (P00–P96) e I51.6: Cardiovascular disease, unspecified (cardiovascular accident NOS) under Other forms of heart disease (I30–I52) of Chapter IX: Diseases of the circulatory system (I00–I99) f Q24.5: Malformation of coronary vessels under Congenital malformations of the circulatory system (Q20–Q28) of Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities (Q00–Q99) Stable ischemic heart disease (SIHD) Ischemic heart disease (IHD) Unstable angina (UA) Acute coronary syndromes (ACS) Non-ST elevation myocardial infarction (NSTEMI) ST elevation myocardial infarction (STEMI) Figure 13.1â•… Conventional classification of ischemic heart disease (IHD) As illustrated, IHD is typically classified into stable IHD (with stable angina as the prototypical clinical manifestation) and acute coronary syndromes (ACS) ACS include unstable angina, non‐ST‐elevation myocardial infarction, and ST‐elevation myocardial infarction 13.2.1.3â•… Definition of CAD and Coronary Heart Diseasê•… CAD and coronary heart disease (CHD) are two most com monly encountered terms in cardiovascular medicine and frequently used synonymously by healthcare professionals However, strictly speaking, there are differences between these two terms CAD is generally used to refer to the path ological process affecting the coronary arteries (usually ath erosclerosis) On the other hand, CHD is actually a result of CAD With CAD, plaque first grows in the coronary arteries until the blood flow to the cardiac muscle is limited This is also called myocardial ischemia It may be chronic, caused by narrowing of the coronary artery and limitation of the blood supply to part of the muscle Or it can be acute, resulting from a sudden plaque rupture Hence, CHD includes the diagnoses yocardial of angina pectoris, myocardial infarction, silent mÂ� ischemia, and CHD mortality that result from CAD Classification, Epidemiology, and Pathophysiology 13.2.2â•… Epidemiology CHD is a major cause of death and disability in developed countries as well as many developing countries, such as China Although CHD mortality rates have declined over the past four decades in the United States (and elsewhere), currently, CHD remains responsible for about one sixth of all deaths in the country The 2014 Heart Disease and Stroke Statistics update of the American Heart Association reported that 15.4 million (or 6.4%) people (age ≥20 years) in the United States have CHD, including 7.6 million with myocardial infarction and 7.8 million with angina pectoris [4] The reported prevalence increases with age for both women and men For individuals aged 40 years in the United States, the lifetime risk of developing CHD is 49% in men and 32% in women Lifetime risk for CHD varies drasti cally as a function of risk factor profiles With an optimal risk factor profile, lifetime risk for CHD is 3.6% for men and 60% of women who die suddenly of CHD have no previous symptoms of this disease People who have had a myocardial infarction have a sudden death rate 4–6 times that of the general population Within years after a first myocardial infarction, at ≥45 years of age, 36% of men and 47% of women will die CHD death rates have fallen from 1968 to the present From 2000 to 2010, the annual death rate attributable to CHD declined 39.2%, and the actual number of deaths declined 26.3% It was estimated that approximately 47% of the decrease in CHD deaths was attributable to treatments (including secondary preventive therapies after myocardial infarction or revascularization, initial treatments for acute myocardial infarction or unstable angina, treatments for heart failure, revascularization for chronic angina, and other therapies such as antihypertensive and lipid‐lowering primary prevention therapies) and approximately 44% was attributable to changes in risk factors (lower total cholesterol, lower blood pressure, lower smoking prevalence, and decreased physical inactivity) NCHS, National Center for Health Statistics; NHANES, National Health and Nutrition Examination Survey; NHLBI, National Heart, Lung, and Blood Institute a Adapted from Ref [4] 250 Overview of Ischemic Heart Disease, Stable Angina, and Drug Therapy The term atherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness) It refers to the process of fatty substances, cholesterol, cellular waste products, calcium, and fibrin (a clotting material in the blood) building up in the inner lining of an artery The resulting buildup is called plaque, which, as noted earlier, is responsible for IHD Plaque may partially or totally block the blood flow through a coronary artery As listed below, two things can happen where plaque occurs: 1.╇ There may be bleeding (hemorrhage) into the plaque 2.╇ A blood clot (thrombus) may form on the plaque’s surface Atherosclerosis is a complex process that begins in childhood Exactly how atherosclerosis begins or what causes it remains partially understood It is generally believed that atherosclerosis starts when the endothelium of the artery becomes damaged Listed below are four possible causes of damage to the arterial wall: 1.╇ Elevated levels of cholesterol and triglycerides in the blood 2.╇ High blood pressure 3.╇ Cigarette smoking 4.╇ Inflammatory and oxidative stress Cigarette smoking greatly aggravates and speeds up the growth of atherosclerosis in the coronary arteries, the aorta, and the arteries of the extremities Because of the damage, over time, cholesterol, triglycerides, platelets, cellular debris, and calcium are deposited in the artery wall These substances may stimulate the cells of the artery wall to produce other mol ecules, including growth factors and proinflammatory cyto kines This results in more cells accumulating in the innermost layer of the artery wall where the atherosclerotic lesions form These cells accumulate, and many of them divide At the same time, fat builds up within and around these cells They also form connective tissue The innermost layer of the artery becomes markedly thickened by these accumulating cells and surrounding material If the wall is thickened sufficiently, the diameter of the artery will be reduced and less blood will flow, thus decreasing the oxygen supply, which may result in ischemia Often, a blood clot forms and blocks the artery, stop ping the flow of blood If the oxygen supply to the cardiac muscle is reduced, a myocardial infarction can occur On the other hand, if the oxygen supply to the brain is cut off, an ischemic stroke can occur (see Unit VIII) Additionally, if the oxygen supply to the extremities stops, it may cause gangrene 13.3â•… Stable Angina and Drug Targeting 13.3.1â•… Definition and Classification Angina, formally known as angina pectoris, is a term used to describe chest pain Along with chest pain, individuals may also feel a sensation of pressure or tightness in the chest The term angina is derived from a Latin word, meaning “to choke.” The angina pain may be felt in the jaw, arm, neck, back, or shoulder as well Angina, caused by a reduced amount of oxygen flowing to the heart, is a symptom of IHD and is not a medical condition itself Angina signifies that the affected individual is at a greater risk of suffering from a heart attack or cardiac arrest In addition to the ICD‐10 classification described in Table 13.1, there are various other ways of classification One conventional scheme classifies angina into three cate gories as listed below (also see Table 13.3): 1.╇ Stable angina 2.╇ Unstable angina 3.╇ Variant angina Based on the characteristics of chest pain (Table 13.4), angina is also classified into typical and atypical angina Table 13.3â•… Conventional classification of angina into stable, unstable, and variant angina Classification Characteristics Stable angina Stable angina is chest pain that typically occurs when an individual suffering from CAD increases the oxygen demand on the heart With CAD, the blood vessels that supply blood and oxygen to the heart are weakened or blocked The relative lack of oxygen delivered to the heart causes the angina Stable angina is predictable because it is generally provoked by exertion or emotional stress Stable angina is relieved by rest or nitroglycerin (see Chapter 11) Unstable angina Unstable angina occurs when the chest pain begins to last longer than 15â•›min, comes on without warning, and does not respond well to rest and medication Unstable angina is associated with an increased risk of an impending heart attack The pain may change in severity once unstable angina occurs Variant angina Variant angina, also referred to as Prinzmetal angina or vasospasm angina, is a rare form of angina An individual experiences variant angina after a spasm in one of the coronary arteries If a coronary artery suddenly spasms, the vessel narrows and decreases the blood supply to the heart Risk factors such as smoking, high blood pressure, high cholesterol, and cold temperatures increase the chance of developing coronary artery spasms This type of angina pain occurs during rest, usually between the hours of midnight to 8â•›a.m and lasts for 5–30â•›min Variant angina is relieved by nitroglycerin Stable Angina and Drug Targeting 251 Table 13.4â•… Traditional clinical classification of chest pain into typical and atypical angina [3, 8] Typical angina (definite) Meets all three of the following characteristics: Substernal chest discomfort of characteristic quality and duration Provoked by exertion or emotional stress Relieved by rest and/or nitrates within minutes Atypical angina (probable) Meets of the three typical anginal characteristics Nonanginal chest pain Meets or none of the three typical anginal characteristics O2 supply Drugs to increase O2 supply Nitrates Calcium channel blockers (CCBs) Others O2 supply O2 demand Drugs to decrease O2 demand β-Blockers Nondihydropyridine CCBs Others O2 demand Figure 13.2â•… Pathophysiological basis of drug targeting in stable angina Angina occurs when myocardial oxygen demand is not met by oxygen supply Drugs that increase myocardial oxygen supply and/or decrease myocardial oxygen demand are used to treat stable angina Typical angina and atypical angina are also known as definite and probable angina, respectively 13.3.2â•… Pathophysiology and Drug Targeting Section 13.2.3 describes the overall pathophysiology of IHD, emphasizing the fundamental causal role of atheroscle rosis in disease development This section discusses the pathophysiology of stable angina, which serves as a basis for understanding antianginal drug targeting 13.3.2.1â•… Pathophysiologyâ•… The pathophysiology of stable angina can be understood from two different aspects: (1) myocardial oxygen imbalance and (2) histological characteristics of atheroma Myocardial Oxygen Imbalancê•…Under physiological conditions, myocardial oxygen demand and supply are balanced Angina is caused by disturbance of this balance, characterized by myocardial oxygen demand exceeding oxygen supply or oxygen supply failing to meet the oxygen demand (Fig 13.2) Hence, an understanding of the patho physiology of angina first requires a brief review of the determinants of myocardial oxygen demand and supply: õ Myocardial oxygen demand: There are four major factors that determine myocardial work and therefore myocardial oxygen demand: (1) heart rate; (2) systolic arterial blood pressure, which determines the afterload of the heart; (3) myocardial wall tension or stress, which is the product of ventricular end‐diastolic volume (preload) and myocardial muscle mass; and (4) myo cardial contractility Clinical conditions associated with an increase in myocardial oxygen demand must affect one or more of these parameters Examples include increased sympathetic activity, as with physical exertion or mental stress, environmental stress (such as cold weather and pollution), tachycardia of any etiology, high blood pressure, and left ventricular hypertrophy õ Myocardial oxygen supply: The major determinants of oxygen supply are the oxygen‐carrying capacity of the blood, which is affected by a variety of factors, 252 Overview of Ischemic Heart Disease, Stable Angina, and Drug Therapy including (i) oxygen tension and the hemoglobin concentration; (ii) the degree of oxygen unloading from hemoglobin to the tissues; and (iii) the coronary artery blood flow, which is in turn determined by coronary artery diameter and tone, collateral blood flow, coro nary perfusion pressure, blood flow within the endocar dium (determined by the left ventricular end‐diastolic pressure), and heart rate (coronary artery flow primarily occurs during diastole) Although any clinical setting that reduces myocardial oxygen supply can cause ischemia and angina, the predominant cause is the epicardial coronary atherosclerosis that limits the coronary blood flow Histological Characteristics of Atheromâ•… In patients with stable angina, the epicardial atherosclerotic lesions, as compared with those of patients with ACS, less commonly show an erosion or rupture of the endothelial lining; the lesions are typically fibrotic, poorly cellular, and with small necrotic cores, thick fibrous caps, and little or no overly ing thrombus In contrast, culprit lesions of ACS patients typically show the rupture or tear of a thin fibrous cap, with exposure toward the lumen of large, soft, prothrombotic, and necrotic core material (containing macrophages, cholesterol clefts, debris, inflammatory cell infiltrates, neovascularÂ� ization, and/or intraplaque hemorrhage) that can trigger occlusive or subocclusive thrombosis [3, 9] 13.3.2.2â•… Drug Targetingâ•… Various classes of drugs have been used to treat stable angina based on the current under standing of its pathophysiology (Fig 13.2) Chapter 14 provides a detailed discussion of the major classes of anti anginal drugs with an emphasis on the pharmacological basis of their use to treat stable angina These drugs are also used in the management of unstable angina as well as other cardiovascular disorders Briefly, drugs used to treat stable angina include those that (i) directly decrease oxygen demand (β‐blockers, calcium channel blockers), (ii) directly increase oxygen supply (organic nitrates, calcium channel blockers), and (iii) act via novel mecha nisms (e.g., ranolazine) 13.4â•… Summary of Chapter Key Points õ IHD is the single most important cause of death world wide It is an umbrella term that refers to a spectrum of cardiac disorders caused by myocardial ischemia, with notable examples including SIHD/stable angina and ACS Atherosclerosis is the fundamental pathophysioư logical basis of IHD õ Angina occurs when myocardial oxygen demand exceeds oxygen supply (i.e., myocardial ischemia) Stable angina is the prototypical manifestation of SIHD (also known as SCAD), predominantly caused by the narrowing of coronary arteries due to atherosclerosis õ Pharmacological therapy for stable angina involves the use of drugs that directly decrease myocardial oxygen demand, directly increase oxygen supply, or act via novel mechanisms These various classes of drugs in treating stable angina are considered in Chapter 14 13.5â•… Self‐Assessment Questions A 56‐year‐old male presents to the physician’s 13.5.1 office, complaining of chest tightness and pain upon exertion or emotional stress The symptoms are relieved by resting or taking sublingual nitro glycerin The patient most likely has which of the following disorders? A.╇ Acute coronary syndrome B Cardiomyopathy C Nonanginal chest pain D Stable ischemic heart disease E Unstable angina 13.5.2 A 65‐year‐old female presents to the physician’s office, complaining of chest pain upon exertion, which can be completely relived by sublingual nitroglycerin Which of the following is most likely the pathophysiological mechanism underlying the patient chest pain? A.╇ Coronary atherosclerosis B Diabetes mellitus C Emphysema D High blood HDL cholesterol E Hypertension 13.5.3 Stable angina occurs as a result of disturbance of the balance between myocardial oxygen supply and oxygen demand Which of the following conditions would most likely aggravate a person’s angina? A.╇ Decreased arterial blood pressure B Decreased cardiac preload C Decreased heart rate D Decreased hemoglobin concentration E Decreased myocardial contractility 13.5.4 A 65‐year‐old man is diagnosed with stable coro nary artery disease of years of duration Which of the following would be the least likely presentation of the patient’s condition? A.╇ Chronic stable angina B Hypotension C Microvascular angina D Substernal chest discomfort 462 Index Isosorbide, see Osmotic diuretics Isosorbide dinitrate, see Nitrates Isosorbide mononitrate, see Nitrates Isradipine, see Calcium channel blockers Ivabradine for treating heart failure, 359 for treating stable angina, 258–9 structure of, 256f JNC7, 119, 120t, 217, see also Hypertension (management guidelines) JNC8, 219, 220, see also Hypertension (management guidelines) K+ATP channel openers, 209–10, see also Vasodilators adverse effects and drug interactions of, 210 chemistry and pharmacokinetics of, 209f, 210 clinical uses of, 210 for treating hypertension, 210 mechanisms and pharmacological effects of, 210 therapeutic dosages of, 210 Labetalol, see Beta-Adrenergic receptor antagonists Lepirudin, see Direct thrombin inhibitors Levosimendan, for treating heart failure, 359, see also Calcium-sensitizing agents Lidocaine, see Antiarrhythmics (class IB) Lipoproteins, 45–51 classification of, 46–47, 46t definition of, 45 enterohepatic circulation of, 48 metabolism, 47–51, 47f, 48f reverse cholesterol transport of, 48–51, 48f structure of, 45–6, 46f, 46t Lisinopril, see ACE inhibitors Lomitapide, for treating HoFH, 80–82, 81f Long-QT syndrome, drug therapy for, 422t Loop diuretics, 134–8 adverse effects and drug interactions of, 137 chemistry and pharmacokinetics of, 134, 135f, 135t clinical uses of, 136, 137 for treating heart failure, 136, see also Heart failure (drugs for) mechanisms and pharmacological effects of, 134, 135f, 136 therapeutic dosages of, 137, 137t Losartan, see Angiotensin receptor blockers Lovastatin, see Statins Lovaza (Omega-3-acid ethyl esters), see Omega-3 Fatty acids Low-density lipoprotein (LDL), see Lipoproteins Low-molecular-weight heparins (LMWHs), see Heparins LQTS, see Long-QT syndrome Macitentan, see Endothelin receptor antagonists Magnesium, for treating arrhythmias, 407–8 Mannitol, see Osmotic diuretics Methazolamide, see Carbonic anhydrase inhibitors Methyldopa, see Centrally acting sympathyolitics Metolazone, see Thiazide diuretics Metoprolol, see Beta-Adrenergic receptor antagonists Mexiletine, see Antiarrhythmics (class IB) Microsomal triglyceride transfer protein (MTP) biochemistry of, 89 inhibitors of, 89 Microvascular angina, see Stable angina Million Hearts initiative goals of, 14, 15t strategies of, 14 Milrinone, see Phosphodiesterase inhibitors Minoxidil, see K+ATP channel openers Mipomersen, for treating HoFH, 82–3, 81f Mixed hyperlipidemia, 51, 52t, see also Dyslipidemias Moexipril, see ACE inhibitors Myocardial infarction, see NSTEMI, STEMI n-3 Fatty acids, see Omega-3 Fatty acids Nebivolol, see Beta-Adrenergic receptor antagonists Neuroprotection definition of, 439 drugs for, 439–41, 440f Neurorepair, for stroke, 442 Niacin, 75–80 activation of GPR 109a, 76f, 77 adverse effects and drug interactions of, 78–9 chemistry and pharmacokinetics of, 76 clinical uses of, 77–8 for treating hypertriglyceridemia, 77 for treating low HDL cholesterol, 77–8 mechanisms and pharmacological effects of, 76–7, 76f therapeutic dosages of, 78 Nicardipine, see Calcium channel blockers Niemann-Pick C1-Like (NPCILI), 69, 70f Nifedipine, see Calcium channel blockers Nimodipine, see Calcium channel blockers Nisoldipine, see Calcium channel blockers Nitrates, 194–201, see also Vasodilators adverse effects and drug interactions of, 200, 201 chemistry and pharmacokinetics of, 196–7, 196f, 197t clinical uses of, 199 for treating acute coronary syndromes, 199 for treating heart failure, 199 for treating stable angina, 199 mechanisms and pharmacological effects of, 197–8, 198f therapeutic dosages of, 200, 200t Nitroglycerin, see Nitrates Nitroprusside, 196–201, see also Vasodilators adverse effects and drug interactions of, 201 chemistry and pharmacokinetics of, 196–7, 196f, 197t clinical uses of, 199 for treating heart failure, 199 for treating hypertension emergency, 199 mechanisms and pharmacological effects of,198, 198f therapeutic dosages of, 200, 200t Noncommunicable diseases (NCD) definition of, 7b global status of, 7, 7f, 9f index Non-ST-elevation myocardial infarction (NSTEMI) definition of, 277, 278f, see also Acute coronary syndromes management guidelines of, 310–324, see also Unstable angina NSTEMI, see Non-ST-elevation myocardial infarction Olmesartan, see Angiotensin receptor blockers Omega-3 fatty acids, 86–8 adverse effects and drug interactions of, 88 cardiovascular effects of, 87 chemical structures of, 86f clinical uses of, 87 for treating hypertriglyceridemia, 87 definition of, 86 mechanisms and pharmacological effects of, 87, 87f preparations of, 86–7 therapeutic dosages of, 88 Organic nitrates, see Nitrates Osmotic diuretics, 142t PCSK9, see Proprotein convertase subtilisin/kexin type PDE3 inhibitors, see Phosphodiesterase inhibitors PDE5 inhibitors, see Phosphodiesterase inhibitors Perhexiline for stable angina, 258 structure of, 256 Perindopril, see ACE inhibitors Peroxisome proliferator-activated receptor-alpha (PPAR-α), 73f, 74 Phamacogenetics/Pharmacogenomics definition of, 29, 30b mechanisms of, 29, 30f Pharmacology definition of, 21–2, 22t historical figures of, 22, 23f, 23t, 24t history of, 22–4, 23t, 24t paradigm of, 24, 25f specialties of, 32, 34t Phosphodiesterase (PDE3) inhibitors, 359, see also Positive inotropic agents adverse effects and drug interactions of, 359 chemistry and pharmacokinetics of, 355f, 359 clinical uses of, 359 for treating heart failure, 359 mechanisms and pharmacological effects of, 359 therapeutic dosages of, 359 Phosphodiesterase (PDE5) inhibitors, 204–7, see also Vasodilators adverse effects and drug interactions of, 206–7 chemistry and pharmacokinetics of, 205, 206f, 206t clinical uses of, 205–6 for treating erectile dysfunction, 205–6 for treating pulmonary arterial hypertension, 206 mechanisms and pharmacological effects of, 205, 206f therapeutic dosages of, 206, 206t Phytosterols and phytostanols, 83–6 adverse effects and drug interactions of, 85 clinical uses of, 84–5 for reducing LDL cholesterol 84 463 definition and chemistry of, 83, 84f dietary supplementation of, 83 historical overview of, 83 mechanisms and pharmacological effects of, 83–4, 85f therapeutic dosages of, 85 Pitavastatin, see Statins Platelet inhibitors, 295–304 classification of, 295–6 cyclooxygenase inhibitors, see Cyclooxygenase inhibitors GP IIb/IIIa antagonist, see Glycoprotein (GP) IIb/IIIa antagonists P2Y12 ADP-receptor antagonists, see P2Y12 ADP-receptor antagonists thrombin receptor antagonists, see Thrombin receptor antagonists Polypill for cardiovascular diseases, 35 definition of, 35 Positive inotropic agents, 354–60 classification of, 354–5 for treating heart failure, see Heart failure Potassium-sparing diuretics, 138–42 adverse effects and drug interactions of, 141 chemistry and pharmacokinetics of, 138, 138f, 139t clinical uses of,140–141 for treating heart failure, 140 for treating hyperaldosteronism, 141 for treating hypertension, 140 mechanisms and pharmacological effects of, 139–40, 139f therapeutic dosages of, 141, 141t Prasugrel, see P2Y12 ADP-receptor antagonists Pravastatin, see Statins Prehypertension definition of, 120t management of, 234–5 Procainamide, see Antiarrhythmics (class IA) Propafenone, see Antiarrhythmics (class IC) Propranolol, see Beta-Adrenergic receptor antagonists Proprotein convertase subtilisin/kexin type (PCSK9) biochemistry of, 89–90, 90f inhibitors of, 89–90 Protein therapeutics for cardiovascular diseases, 35 definition of, 35 Pulmonary hypertension, 235–7 classification of, 236t pathophysiology of, 235 pharmacological management of, 235–7, 237t P2Y12 ADP-receptor antagonists, 297–300 adverse effects and drug interactions of, 300 chemistry and pharmacokinetics of, 298, 298f, 299t clinical uses of, 298, 299t mechanisms and pharmacological effects of, 298, 298f therapeutic dosages of, 298, 299t Quinapril, see ACE inhibitors Quinidine, see Antiarrhythmics (class IA) 464 Index RAAS Inhibitors, 161–81 classification of, 162, 164t drug targeting of, 162, 164t Ramipril, see ACE inhibitors Ranolazine, 255–258 adverse effects and drug interactions of, 257–8 chemistry and pharmacokinetics of, 255, 256f clinical uses of, 257 for treating stable angina, 257 mechanisms and pharmacological effects of, 255–7, 257f therapeutic dosages of, 257 Reentry definition of, 384 electrophysiology of, 384–5, 386f, 387, 387f Refractory angina, see Stable angina Renin-angiotensin-aldosterone system (RAAS) biochemistry of, 162, 162f, 163f historical overview of, 161 inhibitors, see RAAS inhibitors Resistant hypertension definition of, 232 management of, 232 Reteplase, see Thrombolytic agents Riociguat, see Soluble guanylate cyclase stimulators Risk prediction, 15–16, 101 Framingham risk score of, 15–16, 16f, 17f Rivaroxaban, see Selective factor Xa inhibitors Rosuvastatin, see Statins SCD, see Cardiac arrest, sudden Selective factor Xa (SFXa) inhibitors, 290–292 adverse effects and drug interactions of, 292 chemistry and pharmacokinetics of, 290, 291f, 291t clinical uses of, 290, 291t mechanisms and pharmacological effects of, 290 therapeutic dosages of, 290, 292, 292t Serelaxin, for treating heart failure, 359 SFXa inhibitors, see Selective factor Xa inhibitors sGC stimulators, see Soluble guanylate cyclase stimulators Sildenafil, see also Phosphodiesterase inhibitors for treating heart failure 359 for treating pulmonary arterial hypertension, see Pulmonary hypertension Simvastatin, see Statins Sitostanol, see Phytosterols and phytostanols Sitosterol, see Phytosterols and phytostanols Sodium nitroprusside, see Nitroprusside Soluble guanylate cyclase (sGC) stimulators, 207–9, see also Vasodilators adverse effects and drug interactions of, 208–9 chemistry and pharmacokinetics of, 207, 208f clinical uses of, 207 for treating chronic thromboembolic pulmonary hypertension, 207 for treating pulmonary arterial hypertension, 207 mechanisms and pharmacological effects of, 207, 208f therapeutic dosages of, 207–8 Sotalol, 402–404 see also Antiarrhythmics (class III) adverse effects and drug interactions of, 403–4 chemistry and pharmacokinetics of, 402, 402f clinical uses of, 403, 404t mechanisms and pharmacological effects of, 399f, 403 therapeutic dosages of, 403, 404t Spironolactone, see Potassium-sparing diuretics Squalene synthase biochemistry of, 59f inhibitors of, 89 Stable angina, see also Angina definition of, 250 drugs for, 254–9 allopurinol, 259, see also Allopurinol beta-blockers, 254, see also Beta-Adrenergic receptor antagonists calcium channel blockers, 255, see also Calcium channel blockers fatty acid oxidation inhibitors, 258, see also Trimetazidine, Perhexiline inhibitors of sinus node pacemaker current, 258–9, see also Ivabradine nitrates, 255, see also Nitrates ranolazine, 255–8, see also Ranolazine management guidelines, 262–73 drug therapy for mortality prevention, 267–9, 268t, 269t, 272f drug therapy for symptom relief, 266–7, 266t, 267t, 272f microvascular, 271, 271t overview of, 262–5, 263t principles of, 265–6, 272f refractory, 272 revascularization, 269, 269t, 270t vasospastic, 271 Stable coronary artery disease, see Stable angina Stable ischemic heart disease, see Stable angina Statins, 56–64 adverse effects and drug interactions of, 63–4 chemistry and pharmacokinetics of, 57–8, 57f clinical uses of, 61–2 for treating dyslipidemia, 61–2 for treating others, 62 history of discovery of, 56–57 mechanisms and pharmacological effects of, 58–61, 59f, 60f nomenclature of, 56 therapeutic dosages of, 62–3, 63t ST-elevation myocardial infarction (STEMI) definition of, 277, 278f, see also Acute coronary syndromes epidemiology of, 327, 328b management guidelines of, 327–39 2013 ACCF/AHA, 330–331, 333–4, 331t–9t, 338–9 overview, 328, 329t principles, 329–30 Stem cell therapy concept of, 36–8, 37f for heart failure, 360 for stable angina, 259 for stroke, 442 index STEMI, see ST-elevation myocardial infarction Streptokinase, see Thrombolytic agents Stroke, see also Cerebrovascular diseases, Ischemic stroke definition and classification of, 429–30, 430t, 432f epidemiology of, 430, 430b, 431t, 432 Sympathetic nervous system inhibitors of, see Sympatholytics overview of, 147–8, 148f, 149f Sympatholytics, 147–59 classification of, 148, 149f, 150 Systems pharmacology, definition of, 34 Tadalafil, see Phosphodiesterase inhibitors Telmisartan, see Angiotensin receptor blockers Tenecteplase, see Thrombolytic agents Thiazide diuretics, 129–34 adverse effects and drug interactions of, 133–4 chemistry and pharmacokinetics of, 129–30, 130f, 130t clinical uses of,131–2 for treating heart failure, 132 for treating hypertension, 132 for treating other conditions, 132 mechanisms and pharmacological effects of, 130–131, 131f therapeutic dosages of, 132, 132t Thrombin receptor antagonists, 300–301 adverse effects and drug interactions of, 301 chemistry and pharmacokinetics of, 300, 301f clinical uses of, 301 mechanisms and pharmacological effects of, 300–301, 301f therapeutic dosages of, 301 Thrombolytic agents, 304–7 adverse effects and drug interactions of, 307 chemistry and pharmacokinetics of, 305–6, 305t classification of, 304 clinical uses of, 306–7 mechanisms and pharmacological effects of, 305f, 306 therapeutic dosages of, 306t, 307 Thyroid hormone analogs, for reducing LDL cholesterol, 89 Ticagrelor, see P2Y12 ADP-receptor antagonists Tinzaparin, see Heparins Tirofiban, see Glycoprotein IIb/IIIa antagonists Tolvaptan, see Antidiuretic hormone antagonists Torsemide, see Loop diuretics Tosades de pointes, drug therapy of, 420t 465 Total cardiovascular diseases, 4–5, 5f tPA, recombinant human, see Thrombolytic agents Trandolapril, see ACE inhibitors Triamterene, see Potassium-sparing diuretics Trimetazidine for stable angina, 258 structure of, 256 UA, see Unstable angina Unfractionated heparins (UFH), see Heparins Unstable angina, see also Angina definition of, 250t, see also Acute coronary syndromes management guidelines of, 310–324 analgesic therapy, 312 anticoagulant therapy, 312, 316t, see also Anticoagulants anti-ischemic therapy, 312, 313t, 314t antiplatelet therapy, 312, 314t–16t, see also Platelet inhibitors coronary revascularization, 318, 318t, 319t long-term management, 323–4 overview, 310–311 principles, 311 specific patient groups, 318–23, 320t–323t Urea, see Osmotic diuretics Urokinase, see Thrombolytic agents Valsartan, see Angiotensin receptor blockers Vardenafil, see Phosphodiesterase inhibitors Vascepa (Icosapent), see Omega-3 Fatty acids Vascular tone, regulation of, 194–6 Vasodilators, classification of, 194 Vasospastic angina, see Stable angina Verapamil, 404–6, see also Calcium channel blockers; Diltiazem Vernakalant, for treating arrhythmias, 408 Very low-density lipoprotein (VLDL), see Lipoproteins Vitamin K antagonists, 285–7, see also Anticoagulants adverse effects and drug interactions of, 286–7 chemistry and pharmacokinetics of, 285, 286f clinical uses of, 286 mechanisms and pharmacological effects of, 285–6, 286f therapeutic dosages of, 286 Vorapaxar, see Thrombin receptor antagonists Warfarin, see Vitamin K antagonists Endogenous pathway Exogenous pathway LDLR LDL Dietary fat HL Vessel s acid Bile erol t les Cho CM CMR IDL VLDL LPL LPL FFA FFA Figure 3.2â•… Endogenous and exogenous pathways of lipoprotein metabolism See text (Sections 3.2.2.1 and 3.2.2.2) for description CM, chylomicron; CMR, chylomicron remnant; HL, hepatic lipase; IDL, intermediate‐density lipoprotein; LDL, low‐density lipoprotein; LDLR, LDL receptor; FFA, free fatty acid; LPL, lipoprotein lipase; VLDL, very‐low‐density lipoprotein Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics, First Edition Y Robert Li © 2015 John Wiley & Sons, Inc Published 2015 by John Wiley & Sons, Inc Acetyl CoA + Acetoacetyl CoA HO CH3 COO– O HMG-CoA 2NADPH + 2H+ SCoA Statins HMG-CoA reductase CoA HO 2NADP+ CH3 COO– OH CH3 CH3 Mevalonate CH3 H3C O O FPP P O O O – – P O O – Squalene Prenylated proteins (Ras, Rho, Rac) H3C CH3 CH3 • Inflammation/ROS • Cell proliferation • Tissue remodeling H Ubiquinone dolichol CH3 H H H HO Cholesterol CH3 • Mitochondrial electron transport • N-Glycosylation Figure 4.2â•… Molecular mechanism by which statins inhibit cholesterol synthesis Statins competitively inhibit HMG‐CoA reductase, a key enzyme in cholesterol biosynthesis Inhibition of HMG‐CoA reductase by statins also decreases protein prenylation, a process that leads to inflammation, reactive oxygen species (ROS) formation, cell proliferation, and tissue remodeling These events play an important part in Â�atherosclerosis Decreased protein prenylation of small G proteins, including Ras, Rho, and Rac, may hence account for theÂ� lipid‐lowering‐independent beneficial effects of statin therapy On the other hand, statin drugs decrease ubiquinone formation, which might partly be responsible for the development of myopathy associated with statin treatment FPP denotes farnesyl pyrophosphate LDL Statins LDL LDL + Cholesterol LDL Protease LDL ar Nucle on cati translo LDLR SREBP (inactive) LDL LDL + LDLR mRNA Decreasing LDL-cholesterol + SREBP (active) SRE S RE LDL LDL LDLR gene L LDL LDL LDL Figure 4.3â•… Molecular mechanism by which statins reduce LDL cholesterol Statin‐induced decreases in cholesterol concentration in hepatocytes result in protease activation Protease activation causes the activation and nuclear translocation of sterol regulatory element‐binding protein (SREBP), which binds to the sterol regulatory element of the LDL receptor (LDLR) gene, leading to increased expression of LDLR Increased LDLR expression on the surface of hepatocytes promotes LDL uptake from plasma, thereby reducing plasma LDL cholesterol CH CH 7-α-hydroxylase BA on xcreti cid e ine a e l t s Bi inte Into acid Bile rption so Reab Cholesterol (CH) Bile acids (BA) Bile acid sequestrants (BAS) Bile acid – BAS complexes Fecal excretion Figure 4.5â•… Molecular mechanism by which bile acid sequestrants reduce cholesterol A significant portion of bile acids (bile salts) secreted into the intestine is reabsorbed and delivered into the liver via portal vein, hence forming enterohepatic circulation of bile acids (BA) Bile acid sequestrants (BAS) bind BA forming complexes that are eliminated in feces The decreased return of BA to the liver causes upregulation of cholesterol (CH) 7‐α‐hydroxylase, the key enzyme in BA synthesis, thereby leading to decreases in CH concentration in hepatocytes As described in Figure 4.3 legend, decreased cholesterol causes increased expression of LDL receptors on the surface of hepatocytes and the subsequent reduction in plasma LDL cholesterol TG ApoB ApoB mRNA ApoB MTP ApoB VLDL LDL O 2´MOE 2´–Deoxy (Supporting RNase activity) HN 2´MOE CF3 CH3SO3H· N G C C T C A G T C T G C T T C G C A CC 20 Mers of phosphorothioate backbone Mipomersen HN O Lomitapide CF3 Figure 4.9â•… Chemical structures and molecular mechanism of action of lomitapide and mipomersen Lomitapide inhibits microsomal triglyceride transfer protein (MTP), an enzyme involved in the assembly of VLDL in the liver Mipomersen is an antisense that targets ApoB mRNA, thereby reducing ApoB synthesis and the subsequent assembly of VLDL Decreased formation of VLDL results in reduction of LDL cholesterol TG denotes triglyceride; 2′MOE denotes 2′‐methoxyethyl Apical membrane Basolateral membrane Amiloride Triamterene + + 3Na+ Na /K ATPase Na+ 2K+ Na+ channel K+ K+ channel Eplerenone Spironolactone HRE AR Aldosterone Figure 7.8â•… Molecular mechanisms of action of potassium‐sparing diuretics Amiloride and triamterene block the activity of the Na+ channels in the apical membranes of the principal cells, whereas eplerenone and spironolactone decrease the biosynthesis of new Na+ channels in these cells via blocking the aldosterone receptors (AR) As illustrated, aldosterone–AR complex binds to the hormone response element (HRE) of the gene encoding the Na+ channel protein, thereby leading to enhanced expression of the Na+ channels Eplerenone and spironolactone competitively block the binding of aldosterone to AR, thereby inhibiting the transcription of the Na+ channel‐encoding gene Since Na+ reabsorption in the principal cells is coupled with K+ secretion, inhibition of the Na+ reabsorption by these diuretic drugs causes decreased K+ excretion Angiotensinogen Prerenin Renin Renin P/R-R Prerenin P/R-R Angiotensin (1–9) ACE2 Angiotensin I (1–10) ACE Neprilysin ACE Angiotensin (1–7) ACE2 Cathepsin D Tonin tPA Cathepsin G CAGE Chymase AT2 activation Aminopeptidase A ACE Aminopeptidases endopeptidases Angiotensin II (1–8) MAS Angiotensin III (2–8) Aminopeptidases A, M Inactive fragments AT1 activation Angiotensin IV (3 8) Aldosterone AT4 activation Aminopeptidases endopeptidases Inactive fragments Figure 9.2â•… The contemporary view of the RAAS The contemporary view emphasizes multiple aspects of the RAAS not recognized in the classical view For example, the catalytic activity of renin increases when bound to the (pro)renin receptors (P/R‐R), and the otherwise inactive prorenin becomes catalytically active when bound to P/R‐R Angiotensin II can be catabolized by angiotensin‐converting enzyme (ACE2) to form angiotensin‐(1–7), another active peptide of this system, which typically opposes the actions of angiotensin II Angiotensin‐(1–7) can also be derived from angiotensin I with angiotensin‐(1–9) as the intermediate Angiotensin II is cleaved into smaller fragments, such as angiotensin‐ (2–8) (also called angiotensin III) and angiotensin‐(3–8) (also called angiotensin IV) by aminopeptidases Most effects of angiotensin II are mediated by the angiotensin receptor type (AT1 receptor); however, angiotensin II can also bind to the angiotensin receptor type (AT2 receptor), whose activation generally exhibits opposing effects on the responses caused by the activation of AT1 receptors and may result in cardiovascular protection Angiotensin‐(1–7) acts via its putative MAS receptor to elicit responses that may also counteract those caused by activation of AT1 receptors by angiotensin II MAS is a proto‐oncogene encoding a G‐protein‐coupled receptor, which has been recently identified as a putative receptor for angiotensin‐(1–7) The ACE2/angiotensin‐(1–7)/MAS receptor axis may represent new possibilities for developing novel therapeutic strategies for the treatment of cardiovascular diseases As shown in the scheme, in addition to angiotensin II, angiotensin III also activates AT1 receptors Angiotensin IV activates AT4 receptors; however, the physiological significance of this receptor activation remains unclear Likewise, the nomenclature and existence of the AT3 receptor and its relationship to MAS receptor remain controversial Prevention of mortality Relief of symptoms Patient education Lifestyle/risk factor modifications Lipids Blood pressure Diabetes Diet Weight control Physical activity Smoking Others Drug Therapy Organic nitrates CCBs β-Blockers Drug therapy Antiplatelet drugs Statins β-Blockers ACEIs/ARBs Other drugs Revascularization Figure 15.1â•… Schematic illustration of guideline‐based management of stable angina/stable ischemic heart disease (SIHD) As illustrated, effective management of stable angina/SIHD requires multiple intertwined efforts, including drug therapy, nonpharmacological approach, lifestyle/risk factor modifications, and patient education These efforts are aimed to relieve the patients’ symptoms and prevent cardiovascular events and mortality, with the latter being the highest priority ACEIs/ARBs, angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers; CCBs, calcium channel blockers Intrinsic pathway XII Extrinsic pathway XIIa Tissue injury Tissue factor XI + XIa IX + IXa + X Xa Va + VIII VII VIIa VIIIa II + + V XIII IIa + IIa XIIIa + + Fibrinogen Fibrin polymers Cross-linked fibrin polymers Vitamin K antagonists: (–) Posttranslational maturation of factors II, VII, IX, and X Heparins: (–) Factors IIa and Xa Selective factor Xa inhibitors: (–) Factor Xa Direct thrombin inhibitors: (–) Factor IIa Figure 17.2â•… Blood coagulation cascades and anticoagulants As illustrated, the intrinsic and extrinsic pathways of coagulation converge with the activation of factor X and the subsequent formation of thrombin (factor IIa), which in turn catalyzes the formation of fibrin, leading to the fibrin clot formation Vitamin K antagonists inhibit the functional maturation of factors II, VII, IX, and X On the other hand, heparins, selective factor Xa, and direct thrombin inhibitors either indirectly or directly inhibit factor Xa and/or thrombin AT III AT III AT III IIa AT III Xa AT Xa III Xa Xa AT III + Xa IIa AT III UFH IIa UFH acting like a catalyst AT III AT III Xa AT III + IIa AT III LMWH IIa Figure 17.4â•… Molecular mechanisms of action of unfractionated heparin (UFH) and low‐molecular‐weight heparins (LMWHs) As illustrated, UFH binds to antithrombin III (ATIII) and facilitates the inactivation of both factors Xa and IIa by ATIII Due to the short chain, LMWHs only primarily facilitate ATIII‐mediated inactivation of factor Xa Abciximab CH3 NH Eptifibatide H2N Tirofiban NH O O HN S O OH O OH H N O N H HN O HN O S O O N S O N H O NH H2N O TxA2 ADP thrombin others HN Activation of GP IIb/IIIa IIb/IIIa IIb/IIIa TxA2 ADP thrombin others Activation of GP IIb/IIIa Fibrinogen Platelet aggregation Figure 17.10â•… Molecular mechanisms of action of GP IIb/IIIa antagonists Abciximab is a monoclonal antibody drug that directly binds (essentially irreversible) to GP IIb/IIIa, preventing fibrinogen‐mediated platelet aggregation Eptifibatide and tirofiban are small molecule drugs that reversibly antagonize fibrinogen binding to the GP IIb/IIIa receptors Also shown in the scheme is the activation of GP IIb/IIIa receptors by TxA2, ADP, thrombin, and other platelet activators Thrombolytics • Alteplase • Reteplase • Tenecteplase • Urokinase Platelet Platelet Platelet Platelet Platelet Platelet Circulating fibrin clot + Plasminogen Platelet Degradation of fibrin matrix Plasmin Platelet Platelet Platelet Platelet Platelet Platelet AttachedPlatelet fibrin clot Figure 17.11â•… Molecular mechanism of action of thrombolytic drugs Thrombolytic drugs stimulate the conversion of plasminogen to plasmin, which then degrades fibrin, leading to thrombus lysis Bundle of his SA node Atrium AV node Perkinje fibers Ventricle Internodal pathways Bypass track (bundle of kent) Left bundle branch ECG Right bundle branch Figure 23.1â•… Cardiac conduction system, action potential, and electrocardiogram (ECG) The cardiac conduction system consists of the sinoatrial (SA) node, atrial ventricular (AV) node, bundle of His, left and right Bundle branches, and Purkinje fibers In addition, internodal pathways connect SA and AV nodes Conduction fibers also travel from the SA node to the left ventricle In some individual, a bypass track connects the right atrium to the right ventricle This accessory pathway also known as bundle of Kent predisposes the individual to the development of Wolff–Parkinson–White syndrome Cardiac muscle fibers ch n Bra d I Br anc hI I c b ch n Bra d a b I a b1 Bra nch II e Unidirectional block c e Figure 23.5â•… Normal and reentrant cardiac electrical pathways Panel A shows a normal impulse (action potential) conduction through a bifurcating pathway to depolarize the different areas of myocardium Panel B shows formation of a reentrant circuit (dashed lines) due to unidirectional block of one of the branch of the bifurcation pathway leading to tachyarrhythmias As illustrated in panel A, a normal impulse arrives at point a, where it travels through the bifurcating pathway (branches I and II) When the impulses travel down branches I and II to arrive at points b and c, respectively, the impulses are able to once again travel in two opposite directions The impulses between b and c canceled each other, whereas as the rest travel to points d and e respectively, they cause excitation of the myocardium in different areas As depicted in panel B, a unidirectional block occurs in branch II due to pathologic factors, such as ischemia Hence, in branch II, the impulse from point a cannot travel to point c, whereas impulses are able to travel from point c to a Because of this unidirectional block in branch II, when the impulse from branch I arrives at point b, it will travel in two directions: one is toward point d as in normal conduction (panel A), and the other toward point b1 because of no impulse from phase II to cancel it When the impulse from point b1 arrives at point c, it will travel in two directions: one through the retrograde conduction along branch II toward point a (reentry), and the other continues toward point e Once the reentered impulse arrives at point a, it will continue to travel along branch I to point b, forming a circuit As illustrated, reentrant conduction results in extra beats, thereby tachyarrhythmias Primary prevention • Antihypertensives • Statins • Other drugs Neurorepair • Stem cell therapy • Other novel therapies Acute treatment • Thrombolytics • Other drugs Neuroprotection • Edaravone • Other neuroprotectants Long-term neuroprotection • Novel neuroprotectants Secondary prevention • Aspirin • Other drugs Figure 26.3â•… Management options for the preventive and therapeutic intervention of ischemic stroke As depicted, pharmacological therapies play an important part in the overall management of ischemic stroke Of note is the fact that at present neuroprotection and neurorepair are largely experimental approaches whose clinical efficacy remains to be established Edaravone (structure shown in Fig. 27.1) is a free radical scavenging agent that is approved for treating ischemic stroke in Japan WILEY END USER LICENSE AGREEMENT Go to 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Cardiol 20 07 Dec 4; 50 (23 ) :22 64–74 Circulation 20 12 Dec 18; 126 (25 ):e354–471 J Am Coll Cardiol 20 12 Dec 18; 60 (24 ):e44–164 Eur Heart J 20 06 Jun; 27 (11):1341–81 Eur Heart J 20 13 Oct; 34(38) :29 49–3003... on Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics, First Edition Y Robert Li © 20 15 John Wiley & Sons, Inc Published 20 15 by John Wiley & Sons, Inc 26 2 Introduction... symptomatic ischemic cardiomyopathy [3] Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics, First Edition Y Robert Li © 20 15 John Wiley & Sons, Inc Published 20 15